KR101294648B1 - Coated solid preparation - Google Patents

Abstract

This invention aims at the coating solid preparation which can be applied to the monosaturation preparation which the stability of the valproic acid or its pharmacologically acceptable salt containing to humidity, and was deliquestable was suppressed even in an unpackaged state. . The present invention contains valproic acid or a pharmacologically acceptable salt thereof as an active ingredient, is coated with a coating layer containing polyvinyl alcohol and swellable clay, and the mass ratio of polyvinyl alcohol and the swellable clay is 8: 2 to 3 : 7, the swellable clay provides a coated solid preparation dispersed as a laminated structure.

Description

Coated Solids {COATED SOLID PREPARATION}

The present invention relates to a coating solid preparation.

Valproic acid is useful as an antiepileptic drug and is widely used to treat epilepsy and prevent seizures. However, since valproic acid has very high hygroscopicity and is deliquesced only by leaving it at room temperature, there is no formulation applicable to monosaturation preparation. For this reason, the development of the formulation which has stability with respect to humidity, and is not deliquescent under normal storage conditions is anticipated.

As a method of improving the deliquescent property of valproic acid, the method of mix | blending a non-hygroscopic excipient with a solid preparation (patent document 1), the method of performing dragee (patent document 2), the method of film-coating with a polymeric substance ( Patent document 3) and the method of packaging by the packaging material with high vapor barrier property are known.

For example, Patent Document 1 reports a method in which sodium valproate, carbomer, and nonhygroscopic additives are mixed in a uniform state, and the mixture is compressed into tablets. Even when stored for 3 months, it does not absorb more than 5% by weight of water.

Patent Literature 2 discloses a first layer composed of sucrose soluble in water and an organic solvent in sodium valproate, a second layer composed of a polymer and sucrose soluble in water and an organic solvent, a third layer composed of sucrose, and a polymer and sucrose. The refinement | purification which performed the dragee of the 4th layer which consists of other things sequentially is disclosed, and this tablet had stability with respect to humidity.

Patent Document 3 discloses a double coated tablet in which a first coating layer is formed of a coating agent mainly made of starch and sugar, and a second coating layer is formed of a coating agent mainly made of a polymer thereon, and the double coated tablet is an active ingredient. The detoxification of the detoxifying drug contained as was suppressed.

In addition, as a method of packaging with a high vapor barrier property, a solid agent is sealed in a PTP (press through pack) sheet in which polyvinylidene chloride is laminated, and a method of protecting the solid agent from humidity has been used for various chemicals. .

On the other hand, recently, in view of preventing mistakes in the dose of forgetting to take or taking prescribed medicines, saturated preparations are prevalent in each medical field or pharmacy, and a plurality of solid preparations to be taken at one time may be used as PTP sheets or the like. It is becoming mainstream to take out from the packaging material of a package, arrange it in one bag, and provide it to a patient.

Japanese Patent Publication No. 2004-521890 Japanese Patent Publication No. 2006-256961 Japanese Patent Publication No. 2006-83162

However, in the case of mono-saturation preparation, each solid preparation is put into an automatic dispensing machine in an exposure state taken out of the PTP sheet in advance and stored for a long time. It is a phenomenon that application to monosaturation preparation is difficult about this. In other words, patients who are prescribed a formulation containing valproic acid as an active ingredient are desired to be improved in that they do not obtain the advantages of mono-saturated preparations that improve medication compliance and improve the therapeutic effect.

In addition, although there are methods disclosed in Patent Literatures 1 to 3 in order to increase the stability to humidity of the formulation containing sodium valproate, it is difficult to take the patient because neither method can increase the size of the solid preparation by coating. It is a phenomenon that practical use is difficult. In particular, the method of applying sugar to the solid preparation disclosed in Patent Literature 2 has a problem that not only requires a long time for the treatment for sugar drag but also insufficient moisture resistance under high humidity, so that deliquescent liquor cannot be suppressed. In addition, in the double coated tablet disclosed in Patent Literature 3, since the coating process is required a plurality of times, strict control of the manufacturing conditions is required, and it is applied to a formulation containing sodium valproate in both production time and production cost. It is difficult.

Accordingly, an object of the present invention is to provide a coating solid preparation which can be applied to monosaturated preparations in which the valproic acid or its pharmacologically acceptable salt contained in the unpacked state is kept stable against humidity and suppressed deliquescent properties. will be.

In order to achieve the above object, the present inventors have intensively studied to increase the size of the coated solid preparation by coating a coating agent containing a specific component in a specific state on a solid preparation comprising valproic acid or its pharmacologically acceptable salt as an active ingredient. It has been found that a coating solid formulation can be obtained without significantly improving the stability against humidity (without disturbing the patient's dose of the coating solid formulation).

That is, the present invention contains valproic acid or a pharmacologically acceptable salt thereof as an active ingredient, and is coated with a coating layer containing polyvinyl alcohol and swellable clay, and the mass ratio of polyvinyl alcohol and the swellable clay is 8: 2. ˜3: 7, wherein the swellable clay provides a coated solid formulation that is dispersed as a laminate structure.

Since the coating layer becomes a thin coating layer, it does not interfere with the taking of the patient's coating solid formulation, and the swellable clay is sufficiently dispersed in a swelled state as a laminated structure, thereby exhibiting a sufficient maze effect, thereby improving stability of the coating solid formulation against humidity. In addition to this, it is possible to effectively prevent the degradation of valproic acid or its pharmacologically acceptable salt.

It is preferable that the said swellable clay is bentonite or magnesium aluminum silicate, and it is preferable that the water vapor permeability of the said coating layer is 1.0 * 10 <^-5> -1.0 * 10 <^-4> g / cm <2> * 24hr * atm.

Since bentonite and magnesium aluminum silicate have very large aspect ratios, a greater maze effect can be generated in the coating layer formed on the surface of the solid preparation to further increase the stability of the coated solid preparation to humidity.

(Effects of the Invention)

According to the present invention, it is possible to provide a coating solid preparation which can be applied to monosaturated preparations in which the valproic acid or its pharmacologically acceptable salt contained in the unpacked state is kept stable against humidity and whose deliquescent is suppressed. Can be. Moreover, since the coating layer of the coating solid preparation of this invention becomes a thin film layer, it does not interfere with the taking of the coating solid preparation of a patient, and since a swellable clay disperse | distributes as a laminated structure in a swollen state, it exhibits the maze effect fully. In addition to enhancing the stability of the coated solid preparation to humidity, it is possible to effectively prevent deliquescent valproic acid or its pharmacologically acceptable salts. In addition, the coating solid preparation of the present invention can be used not only for sustained release preparations but also for immediate release preparations because of its excellent stability against humidity and excellent disintegration.

1 is a focused ion beam transmission electron microscope image of the film of Example 1. FIG.
2 is a focused ion beam transmission electron microscope image of the film of Comparative Example 2. FIG.

EMBODIMENT OF THE INVENTION Hereinafter, preferable embodiment for implementing this invention is described. However, this invention is not limited to the following embodiment, Unless specifically stated, "%" shows the "mass to mass percentage (w / w%)."

The coating solid preparation of the present invention contains valproic acid or a pharmacologically acceptable salt thereof as an active ingredient, and is coated with a coating layer containing polyvinyl alcohol and swellable clay, and the mass ratio of the polyvinyl alcohol and the swellable clay is 8: 2 to 3: 7, wherein the swellable clay is dispersed as a laminated structure.

"Solid formulations" are medicines formulated to be solid, for example, tablets (including sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, granules, powders, pills , Torokee, film, etc. are mentioned. The "coating solid preparation" refers to a preparation in which a coating layer is formed on the surface of the solid preparation by coating with a coating agent to prevent the active ingredient from being decomposed by oxygen, steam, light, or the like.

Examples of `` valproic acid or a pharmacologically acceptable salt thereof '' include valproic acid, sodium valproate, sodium semivalproate, sodium divalproate, divalprox, magnesium valproate, zinc valproate and valpro Potassium acid and lithium valproate can be illustrated, and commercially available formulations of sodium valproate include selenica tablets (manufactured by Kowa Company, Ltd.), selenica R tablets (manufactured by Kowa Company, Ltd.) and selenica R granules. (From Kowa Company, Ltd.), valerian (from Dainippon Sumitomo Pharma Co., Ltd.), high serenine (from Schering-Plough Corporation), Defaken (from Kyowa Hakko Co., Ltd.), Depaken R tablets (manufactured by Kyowa Hakko Co., Ltd.) and Depaken fine grains (manufactured by Kyowa Hakko Co., Ltd.) may be exemplified as depacot tablets (Abbott product) as commercially available formulations of Devalprox.

The term "polyvinyl alcohol" refers to an alcohol obtained by saponifying polyvinyl acetate, and includes from partially saponified polyvinyl alcohol in which several ten percent of acetic acid groups remain to fully saponified polyvinyl alcohol in which only a few% of acetic acid groups remain. 70-97 mol% is preferable, as for the saponification degree of polyvinyl alcohol, 200-3000 are preferable and, as for average polymerization degree, 600-2400 are more preferable.

Moreover, you may use the said polyvinyl alcohol in mixture of 2 or more types of polyvinyl alcohol from which a saponification degree and average polymerization degree differ. When mixing two or more types of polyvinyl alcohol, what is necessary is just to add the thing of the low polymerization degree, for example, and to mix the thing of the high polymerization degree subsequently. Examples of polyvinyl alcohols include various foams (manufactured by Kuraray Co., Ltd.) and gosenol (manufactured by Nippon Synthetic Chemical Industry Co., Ltd.).

The term "swellable clay" refers to a clay having swelling properties, but more specifically, a substance having swelling properties among fine powders that exhibit viscosity and plasticity when an appropriate amount of water is included. The swellable clay is preferably charged with a negative charge from the composition balance of the metal salt species, and can illustrate smectite such as hydrous aluminum silicate having a three-layer structure. Charging to negative charge refers to a state in which the swellable clay has a cation exchange capacity, and the charge amount is expressed as a cation exchange capacity (CEC). Incidentally, the unit of cation exchange capacity is milliquivalents / 100 grams (usually expressed as meq / 100g), and is generally expressed as the equivalent number corresponding to the molar concentration of monovalent ions. As swellable clay contained in the said coating layer, hydrous aluminum silicate which has a three-layered structure is preferable, and smectite can be illustrated. Smectite includes beadelite, nontronite, saponite, hectorite, souconite, bentonite, magnesium aluminum silicate and the like, and can be used alone or in combination of two or more thereof. In smectite, bentonite and magnesium aluminum silicate are preferable, and bentonite is more preferable. Further, the swellable clay may be used in combination as long as the swellable clay is within a range in which the stability against humidity of valproic acid or its pharmacologically acceptable salt is not lowered.

The "swelling clay in a swelling state" refers to a swellable clay in a state in which water is contained in the swellable clay and is swollen. For example, swellable clay in a dispersed state such that the swellable clay is suspended in a dispersion medium such as water and stirred with a homogenizer or the like can be completely filtered through a filter paper is preferable as the swellable clay in a swelling state. As filter paper to be used, for example, No. 5B quantitative filter paper (ADVANTEC product) is more preferable.

The swellable clay is preferably dispersed as a laminate structure. The "laminated structure" refers to a laminated structure in which a plurality of layered structures are laminated, and specifically refers to a laminated structure in which 10 to 100 layers of band-like materials of swellable clay are laminated. In order for the said swellable clay to form a laminated structure, swellable clay may be disperse | distributed in a coating agent in a swollen state, and the surface of a solid agent may be coat | covered with this coating agent.

A "coating layer" is a coating layer formed by coating a coating agent on a solid agent, and is a layer for preventing the active ingredient contained in the solid agent from being decomposed by oxygen, water vapor, light or the like. This coating layer contains the said polyvinyl alcohol and swellable clay, It is preferable that the mass ratio of polyvinyl alcohol and swellable clay is 8: 2-3: 7, and it is more preferable that it is 4: 6-6: 4. If the mass of the swellable clay is less than a quarter of the mass of the polyvinyl alcohol, the maze effect of the swellable clay is reduced, and stability to the humidity of valproic acid or its pharmacologically acceptable salt cannot be sufficiently obtained. This is because if the mass of clay exceeds 2.3 times the mass of polyvinyl alcohol, the proportion of the swellable clay is too high, resulting in uneven layer structure of the coating layer and sufficient barrier property cannot be obtained. Moreover, it is preferable that the ratio of swellable clay in the said coating layer is 5% or more with respect to the whole coating layer.

The water vapor permeability of the coating layer is preferably 1.0 × 10 ⁻⁵ to 1.0 × 10 ⁻⁴ g · mm / cm 2 · 24hr · atm, and preferably 1.0 × 10 ⁻⁵ to 6.0 × 10 ^-5 g · mm / cm 2 · 24hr · It is more preferable that it is atm, and it is especially preferable that it is 1.0 * 10 <^-5> -3.5 * 10 <^-5> g * mm / cm <2> * 24hr * atm.

The measurement of the water vapor transmission rate may be performed according to JIS K8123 (1994), which is a standard standard of the technical field, for example. However, as described in the examples of the present application, this method may be appropriately partially modified and measured.

The coating agent used to form the coating layer includes the polyvinyl alcohol and the swellable clay, and is prepared by dispersing in a suitable solvent according to the purpose of use to contain valproic acid or a pharmacologically acceptable salt thereof as an active ingredient. Solid preparations can be coated.

As a solvent used for preparation of a coating agent, water, an organic solvent, and a water-organic solvent mixing system can be illustrated, Water is especially preferable. As an organic solvent, C1-C5 lower alcohol or these mixed solvent can be illustrated.

Preferably, the coating layer is coated with the coating agent in an amount of 2 to 200%, and when the solid agent is in tablet form, the coating amount is preferably 3 to 30%, more preferably 3 to 20%, and 3 10% is more preferable.

As a coating method of the coating agent to a solid preparation, the method of using a coating pan, a tablet coating machine, etc. is mentioned, for example, if an inner layer is tablet form, The method of using a fluidized bed coater, an electric fluidized bed coater, etc. is mentioned if it is granular or powder form. Can be.

You may further add the additive normally used by those skilled in the art to the said coating layer and coating agent. As such an additive, coloring agents, such as a plant extract pigment | dye, and shielding agents, such as titanium oxide, calcium carbonate, and silicon dioxide, are mentioned.

A pharmaceutically acceptable additive may be added to the coating solid preparation so long as the stability to humidity of valproic acid or its pharmacologically acceptable salt does not decrease. For example, a surfactant may be added to improve the dispersibility of the swellable clay.

Moreover, as a coating agent used for the said coating layer or coating in order to impart disintegration property of a coating solid agent, for example, maltose, maltitol, sorbitol, xylitol, fructose, glucose, lactitol, isomaltose, lactose, erythritol And sugar alcohols such as mannitol, trehalose or sucrose, disintegrating agents such as croscarmellose sodium and low-substituted hydroxypropyl cellulose may be added, and the coating agent used for the coating layer or coating in order to increase the strength of the coating solid preparation. You may add plasticizers, such as triethyl citrate, polyethyleneglycol, and glycerol, to it.

However, attention should be paid to the addition amount of the additive commonly used by those skilled in the art, the pharmaceutically acceptable additive, the disintegrating agent, the plasticizer and the like. As mentioned above, it is important for this invention to be a coating layer which forms the laminated structure by which 10-100 layer of swelling clay strips were laminated | stacked, The said strip | belt-shaped thing has a contact surface, without swelling clay being interrupted continuously in the middle. Point out. When the said additive etc. are added excessively or it is added unevenly, there exists a discontinuous part which swelling clays do not contact, and this discontinuous part exists and the moistureproof performance of a coating layer may fall.

The presence or absence of the discontinuous part by the addition of the said additive can be confirmed by observing the longitudinal section of a coating layer with a transmission electron microscope using the focused ion beam method. That is, when the discontinuous part of swellable clay is observed with respect to the thickness direction of a coating layer, there exists a possibility that the moisture proof performance of a coating layer may fall.

The coating solid agent may have another functional coating made of a gas-soluble or enteric polymer material on the outer side of the coating layer, or a gas-soluble or enteric polymer material on the inside of the coating layer. You may have another functional film which consists of a etc.

Example

Hereinafter, although an Example is given and this invention is demonstrated concretely, this invention is not limited by the following example.

(Method of measuring water vapor permeability)

The measurement of water vapor permeability was tested by partially modifying JIS K8123 (1994), which is a standard standard in the technical field. First, the film prepared by the method described below was reflected on light, and the part of uniform thickness without a pinhole was cut out circularly so that the diameter might be 3.5 cm, and the thickness of the film was measured at five arbitrary places.

Next, 3 g of calcium chloride (particle size of 850 to 2000 µm) was placed in an aluminum cup (30 mm in diameter), and the coating film cut in a circle on the aluminum cup and the ring for fixing the film were placed in order. The ring was fixed to rest, and the molten paraffin wax was then poured into the edge of the aluminum cup. After the paraffin wax had solidified, the weight was removed, and the mass of the entire aluminum cup was weighed to obtain the mass at the start. Then, the aluminum cup was put into the thermostat of 40 degreeC * 75% RH, it took out every 24 hours, the mass was measured, and the water vapor transmission coefficient was computed using the following formula | equation. However, in the measurement test of water vapor permeability described below, all were r = 1.5 cm, t = 24 hours, and C = 1atm.

Water vapor permeability P (gmm / cm2, 24hratm) = WA / B

W: mass (g) increased in 24 hours

A: average value (mm) of film thickness of 5 places

B: transmission area πr ² (cm 2)

t: elapsed time (hours)

C: atm

(Example 1)

To 177.5 parts by mass of water, 10.0 parts by mass of polyvinyl alcohol (EG-05; manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) and 312.5 parts by mass of bentonite solution were added, followed by stirring with a homogenizer (Polytron Model KR). Got it. The 3.2% bentonite solution was added with 32 parts by mass of bentonite (Cunipia-F; manufactured by KUNIMINE INDUSTRIES CO., LTD, cation exchange capacity: 115 meq / 100 g) to 968 parts by mass of water, homogeneously dispersed by homogenizer and A suction filtration was used. Hereinafter, polyvinyl alcohol may abbreviate PVA and bentonite as BT, respectively.

When 200 g of sodium valproate sustained-release tablet (Selenica R 200 mg; manufactured by Kowa Company, Ltd.) was put into a coating pan (DRC-200; manufactured by Powrex Corp.), and the coating agent prepared in Example 1 had a thickness of 20 µm. Coated on tablets until. The change in appearance with time of the tablet when the obtained coating solid preparation was left under the condition of 25 ° C.60% RH was observed.

A portion of the coating obtained in Example 1 was taken and spray sprayed on the back side of the polypropylene balance tray and immediately dried in the warm air of a dryer. After repeating spray spraying and dryer drying several times, it was left to stand in a 50 degreeC oven with a balance tray, dried overnight to obtain a film, and the water vapor transmission rate was measured.

(Examples 2 and 3)

As in the configuration shown in Table 1, water, PVA, and BT solutions were mixed to obtain a coating solid preparation by the method of Example 1, and the change in appearance over time of the tablet was observed. Moreover, the film was obtained by the method of Example 1, and water vapor permeability was measured.

(Examples 4 and 5)

Water, PVA, and BT solution were mixed so that it might become the structure shown in Table 1, the film was obtained by the method of Example 1, and water vapor transmission rate was measured.

(Comparative Example 1)

The change in the appearance of the tablet over time when sodium valproate sustained-release tablet (Selenica R 200 mg; manufactured by Kowa Company, Ltd.) was left at 25 ° C.60% RH was observed.

(Comparative Examples 2-4)

Water, PVA, and BT solution were mixed so that it might become the structure shown in Table 1, the coating solid preparation was obtained by the method of Example 1, and the change of the external appearance of a tablet was observed over time. Moreover, the film was obtained by the method of Example 1, and water vapor permeability was measured.

Table 1 shows the presence or absence (deterioration in appearance change) of the tablets obtained from Examples 1 to 3 and Comparative Examples 1 to 4, water vapor permeability, and water vapor permeability of the films obtained from Examples 4 and 5. In addition, the symbol in a table | surface means that the change of (circle) is unchanged and x has confirmed the leaching of the drug prepared to the outside of a tablet.

According to Table 1, when the mass ratio (PVA / BT) of PVA and BT is 8: 2-3: 7, it was possible to suppress the detoxification property of sodium valproate, and to obtain a stable solid preparation. In addition, it was clear from the evaluation of water vapor permeability that the solid preparation coated with the water vapor permeability of the film of 1.0 × 10 ⁻⁴ or less was very stable with respect to humidity.

(Transmission electron microscope measurement of the film)

The longitudinal cross sections of the films of Example 1 and Comparative Example 4 were observed with a transmission electron microscope using the focused ion beam method. The microscope image of Example 1 is shown in FIG. 1, and the microscope image of Comparative Example 4 is shown in FIG.

In FIG. 1, the shape which BT was not interrupted continuously as a laminated structure in a film | membrane, but had a contact surface of BT and was disperse | distributed uniformly was observed. On the other hand, in FIG. 2, BT almost does not form a laminated structure, and since the discontinuous part of BT was observed in the thickness direction of a film (up-down direction in FIG. 2), uniform dispersion of BT laminated structure lowers water vapor permeability. And the stability of the solid preparation against humidity.

(Example 6)

5.28 mass parts PVA, 385.0 mass parts BT solution, and 2.4 mass parts sorbitan monolaurate were added to 17.32 mass parts water and 390.0 mass parts ethanol, and it stirred with the homogenizer and obtained the coating agent. The film was obtained by the method of Example 1, and water vapor permeability was measured. Hereinafter, sorbitan monolaurate may be abbreviated as Span 20.

(Comparative Example 5)

16.0 mass parts PVA and 4.0 mass parts BT were added to 480.0 mass parts water, and it stirred for 15 minutes with the magnetic stirrer, and obtained the coating agent. In Comparative Example 5, BT is different from Example 1 in that it is added without being swollen. The film was obtained from the obtained coating agent by the method of Example 1, and the water vapor transmission rate was measured.

(Comparative Example 6)

To 653.1 parts by mass of water, 22.6 parts by mass of Eudragit RL 30D (registered trademark) (30% aqueous dispersion) (Rohm), 6.8 parts by mass of PVA, and 212.5 parts by mass of BT solution were added, followed by stirring with a homogenizer to obtain a coating agent. The coating solid preparation was obtained by the method of Example 1, and the change in external appearance of the tablet was observed over time. In addition, a film was obtained by the method of Example 1 and water vapor transmission rate was measured.

(Comparative Example 7)

To 736.5 mass parts water, 5.0 mass parts crystalline cellulose, 5.0 mass parts ethyl cellulose, 2.5 mass parts PVA, 125.0 mass parts BT solution, and 1.0 mass parts glycerin fatty acid ester were added, and it stirred with the homogenizer and obtained the coating agent. The coating solid preparation was obtained by the method of Example 1, and the change in appearance over time of the tablet was observed. Moreover, the film was obtained by the method of Example 1, and water vapor permeability was measured.

(Comparative Example 8)

15.0 mass parts PVA and 10.0 mass parts talc were added to 225.0 mass parts water, and it stirred with the homogenizer and obtained the coating liquid. Here, talc is a non-swellable clay mineral. The coating solid preparation was obtained by the method of Example 1, and the change in external appearance of the tablet was observed over time. Moreover, the film was obtained by the method of Example 1, and water vapor permeability was measured.

Table 2 shows the presence or absence (deterioration of appearance) of the tablets obtained in Example 6 and Comparative Examples 5 to 8 and the water vapor transmission rate of the film. In addition, the symbol in a table | surface means that the change of (circle) is unchanged and x has confirmed the leaching of the drug prepared to the outside of a tablet.

As a result of Example 6, when a nonionic surfactant was added to PVA / BT, the water vapor permeability of the film was 1.0 × 10 ⁻⁴ or less, and deliquestable property was not observed even for two weeks of storage. From the comparison between Example 2 and Comparative Example 5, it was found that BT is preferably added in a swollen state, not as a powder. Since the tablets of Comparative Examples 6 and 7 coated with a moisture-proof coating composition (coating agent) made of a water-insoluble substance, water vapor permeability of the coating was greater than 1.0 × 10 ⁻⁴ , and deliquession was observed in two weeks of storage, It has been found that the moisture-proof coating composition using S was not able to sufficiently secure stability against humidity. In addition, it was found by comparison between Comparative Example 8 and Example 5 that moisture-proofing properties were remarkably improved by blending swellable clay.

(Example 7)

The elution test of the tablet which left the coated tablet obtained in Example 6 and this tablet on 25 degreeC60% RH conditions was done. In the dissolution test, tablets were added to 900 mL of distilled water according to the 15th revision of the Japanese Pharmacopoeia Dissolution Test Method 2, and drug dissolution rates at 8 hours, 11 hours, and 20 hours after the start of dissolution were quantified by HPLC.

(HPLC conditions)

Mobile phase: 50 mM sodium dihydrogen phosphate / acetonitrile = 5/5 (v / v)

Column: Devolosil ODS-5 (4.6 × 150 mm)

Detecting Wavelength: 210nm

(Comparative Example 9)

The dissolution test was conducted by the method of Example 7 for the sodium valproate sustained-release tablet (Selenica R 200 mg; manufactured by Kowa Company, Ltd.) and tablets left at 25 ° C.60% RH.

Table 3 shows the dissolution test results of Example 7 and Comparative Example 9.

As a result, in Example 7, it was confirmed that until 4 weeks after storage, the elution value equivalent to the commercially available sustained-release tablet of Selenica R 200 mg (see the start of Comparative Example 9) was shown. On the other hand, in Comparative Example 9, after only 1 day of storage, the elution value significantly increased from the value of Selenica R 200 mg tablet (refer to the start of Comparative Example 9) due to drug dissolution. Therefore, it was found that the solid preparations of the present invention were not only stable to humidity but also had good elution.

(Example 8)

200 g of sodium valproate plain tablet (200 mg of Depaken; manufactured by Kyowa Hakko) was placed in a coating pan (DRC-200; manufactured by Powrex), and the coating agent prepared in Example 1 was coated until the coating thickness was 20 µm. With respect to the obtained coated solid preparation, the change in appearance over time of the tablet when left under the condition of 25 ° C. 60% RH was observed.

(Example 9)

200 g of sodium valproate ordinary tablet (200 mg of Depaken; manufactured by Kyowa Hakko) was placed in a coating pan (DRC-200; manufactured by Powrex), and the coating prepared in Example 6 was coated until the coating thickness was 20 µm. The change in appearance with time of the tablet when the obtained coating solid preparation was left under the condition of 25 ° C.60% RH was observed.

(Comparative Example 10)

The change in the appearance of the tablets over time when sodium valproate ordinary tablets (Depaken 200 mg; Kyowa Hakko) was left under conditions of 25 ° C. and 60% RH was observed.

Table 4 shows the change in appearance over time of the tablets obtained in Example 8, Example 9 and Comparative Example 10. In addition, the symbol in a table | surface means that the change of (circle) is unchanged and x has confirmed the leaching of the drug prepared to the outside of a tablet.

Table 4 shows that the solid preparations of the present invention can be applied not only to slow-release tablets but also to slow-release tablets because deliquescent properties can be sufficiently suppressed even when the inner layer is a regular tablet (fast-release tablet).

(Industrial availability)

The solid preparation of the present invention is useful as a mono-saturable solid preparation because of its excellent long-term stability with respect to the humidity of valproic acid or its pharmacologically acceptable salt and its elution property. By being able to saturate, the medication compliance of a patient improves and it leads to the industrial merit in that it leads to the improvement of a therapeutic effect further.

Claims (3)

Contains valproic acid or a pharmacologically acceptable salt thereof as an active ingredient,
Coated with a coating layer comprising polyvinyl alcohol and swellable clay,
The mass ratio of the polyvinyl alcohol and the swellable clay is 8: 2 to 3: 7,
The swellable clay is bentonite or magnesium aluminum silicate and is dispersed as a laminate structure. delete The method of claim 1,
The water vapor permeability of the coating layer is 1.0 x 10 ^-5 to 1.0 x 10 ^-4 g · mm / cm 2 · 24hr · atm.

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